PROJECT SUMMARY/ABSTRACT: The primary aim of this proposal is to identify multimodality magnetic resonance imaging (MRI) measures of cerebral blood flow (CBF), cortical atrophy, and white matter (WM) abnormalities, which are predictors of, and altered by, psychotherapy treatment response for late life major depressive disorder (LLD). This will contribute to our overall goal, which is to inform the development of new and more effective treatments for LLD. Major depressive Disorder (MDD) is associated with tremendous personal suffering and is the 4th leading contributor to the global burden of disability worldwide. LLD is particularly common and debilitating with up to 15% of adults over the age of 65 suffering from LLD. Both antidepressants and psychotherapy interventions are commonly utilized to treat LLD, however a significant number of individuals do not respond to either type of treatment. Poor treatment outcomes in LLD are often posited to be the result of structural or functional brain abnormalities. In recent years several effective psychotherapies have been designed specifically for LLD but determining the impact of neurobiological factors on psychotherapy response in LLD has not been evaluated. The extant literature and our preliminary data suggest that CBF, cortical atrophy, and WM abnormalities may be important factors contributing to psychotherapy response in LLD. The existing studies, however, have focused on unimodal neuroimaging investigations, i.e. evaluating the impact of one factor such as WM abnormalities on treatment response without evaluating for the effects of other factors. This approach, while useful, limits our ability to clarify the most salient neurobiological factors associated with treatment response and the interrelations of these factors. Utilizing multimodal MRI methods to evaluate several types of MRI data simultaneously offers a significant opportunity to clarify the relative contributions of CBF, cortical atrophy, and WM abnormalities on psychotherapy response in LLD. For this study we will recruit 110 older adults with LLD who are not taking antidepressants. All LLD participants will be enrolled in a 12-week psychotherapy intervention and assessments of depression severity will be conducted during treatment. All participants will participate in MRI and clinical evaluations prior to treatment and again after 12 weeks of treatment. Data for 117 age, gender, and education matched participants without LLD using the same neuroimaging and cognitive assessment protocols will be used to model potential confounding effects of age, gender, and education on MRI measures prior to conducting our primary analyses in LLD participants. Using multimodal MRI analyses (controlling for cognitive functioning and other clinical characteristics) we expect to demonstrate that CBF will show stronger associations with depression treatment response than GM atrophy and WM abnormalities. Further, we expect to show that CBF increases in frontal brain regions with remission of depression. Collectively these findings may have a significant impact on the development of new treatments for LLD.